Folic Acid FIGURE 1: Chemical Structure of Folic Acid [8] By: Linda Kim Andrew Liu Milton Reisis

WHAT IS FOLIC ACID? Folic acid = pteroylmonoglutamic acid, folacin, vitamin Bc, vitamin B9 and Lactobacillus casei factor [8]. Folic acid is a water-soluble B-vitamin [8] MW = 441kDa Must be ingested in diet (cannot be synthesized by body)

WHY IS FOLIC ACID NEEDED? Formation of the coenzyme referred to as tetrahydrofolate (THF) [1] Essential for creating heme, the iron containing substance in haemoglobin [1] Proper formation of the brain, spinal cord, and nerve cells in the embryo. Closure of the neural tube in the fetus cannot be completed without it (Northrup H, 2000). Proper formation of the brain, spinal cord, and nerve cells in the embryo. Closure of the neural tube in the fetus cannot be completed without it (Northrup H, 2000). Northrup H, 2000Northrup H, 2000 Essential for synthesis of serine, methionine, ATP, GTP, thymidylate

ABSORPTION Natural food source (polyglutamate): conjugase in the small intestines lumen converts polyglutamates (low absorption) to monoglutamates for absorption [4] Monoglutamate is readily absorbed from the gut via energy-dependent, carrier-mediated mechanisms, involving membrane-associated folate-binding proteins [4]

DISTRIBUTION Tetrahydrofolate (THF) and its derivatives distribute to all body tissues [4] N5-methyl-THF is the major storage form of folate in the body (i.e. ~50% in liver) [4] N5-methyl-THF is highly bound to albumin [4]

METABOLISM Folate reduced to dihydrofolate (DHF) and then to tetrahydrofolate (THF) within cells, by dihydrofolate reductase (DHFR) and NADH [7] Addition of glutamate residues to THF in the cell keep it within the cell to form its active coenzyme in one-carbon metabolism reactions [7] 5-methyl-THF is formed by the reduction of N5, N10-methylene-FH4 by N5, N10-methylene-THF reductase [7] Normally, folate is excreted in the urine; folate is also excreted in the bile, if not reabsorbed [4]

TABLE 1: One-carbon pool: Sources and Recipients of Carbon [7] SourceForm of THF produced RecipientProduct FormateN10-FormylPurine precursorPurine (C2) HistidineN5, N10-MethenylPurine precursorPurine (C8) Serine, Glycine, Formaldehyde N5, N10-MethylenedUMP Glycine dTMP Serine Reduction of N5, N10-methylene- THF N5-MethylVitamin-B12Methyl-B12

HOW DOES FOLIC ACID WORK? Folic acid is converted to its active coenzyme form, THF, which behaves as a donor or receiver of a one carbon entity in different oxidation states (formyl, methylene, or methyl)

FIGURE 2: FOLATE MECHANISM OF ACTION [9]

FIGURE 3: MECHANISM OF ACTION – EXAMPLE [9]

FIGURE 4: MECHANISM OF ACTION – EXAMPLE [2]

Sources of Folic Acid Cereals ( mcg), dark green vegetables ( mcg), citrus fruits ( mcg) [10] Folic acid may also be found in supplements and multivitamin combinations sold at pharmacies

Folate Deficiency

Causes of Folate Deficiency Decreased intake (diet, malabsorption) Increased need (pregnancy) Also, consider decreased availability (antifolate drugs etc.)

WHAT ARE NEURAL TUBE DEFECTS (NTDs)? The neural tube forms in the embryo and then closes (between the 2 nd and 4 th week of gestation) A neural tube defect occurs when the neural tube fails to close properly The two most common NTDs are anencephaly and spina bifida

What is Spina Bifida? Occurs when the two sides of the spine fail to close and protect the spinal cord There are two forms of spina bifida: 1) Spina bifida occulta (mildest form) 2) Spina bifida manifesta which includes two types of spina bifida: meningocele and myelomeningocele

What is Spina Bifida? Source:

What Causes Spina Bifida? Largely unknown Some evidence suggests that genes may be involved. (Northrup H et al, 2000) genes A high fever during pregnancy or epileptic women who have taken the drug valproic acid to control seizures may have an increased risk of having a baby with spina bifida. (Lewis DP et al, 1998) pregnancy

How Can NTDs be Prevented? All women of childbearing age should receive 0.4 mg (400 micrograms) of folic acid daily prior to conception of planned or unplanned pregnancies and continue thru 1 st trimester Women with a history of NTD and should receive daily supplementation of 4 mg (4000 micrograms) of folic acid starting three months prior to conception and continuing thru the 1 st trimester

References [1] Adams, S.L Biochemical Functions of Folic Acid, accessed January [2] Angstadt, C.N Purine and Pyrimidine Metabolism, accessed January [3] Castillo, E.S Folic Acid, CHEMICAL%20PROPERTIES, accessed January CHEMICAL%20PROPERTIES CHEMICAL%20PROPERTIES [4] Expert Group on Vitamins and Minerals Review of Folic Acid, accessed January [5] Fenech M The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475(1-2): [6] Larsen, H.R Folic Acid: Dont Be Without It!, accessed January [7] Marks, D.B., Marks, A.D., and Smith, C.M Basic Medical Biochemistry: A Clinical Approach., Williams and Wilkins, Maryland, pp [8] No author Folic Acid, accessed January [9] No author Main Folate Metabolism Pathways, accessed January [10] No author CERHR: Folic Acid, accessed January [11] Wolfson, D Pharmaceutical Drugs Deplete Folic Acid, accessed January

References *For NTD section AllRefer Health – Caring for your Well Being: Champel V et al. Should folic acid be given to women treated with valproic acid and/or carbamazepine? Folic acid and pregnancy in epilepsy. Rev Neurol Mar; 155(3): Geisel J. Folic acid and neural tube defects in pregnancy: a review. J Perinat Neonatal Nurs Oct-Nov; 17(4): Lewis DP et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother Jul-Aug; 32(7-8): Lewis DP et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Improvement with folic acid. Ann Pharmacother Sep; 32(9): Review. MEDLINEplus – Spina Bifida: MEDLINEplus – Folic Acid: Northrup H et al. Spina bifida and other neural tube defects. Curr Probl Pediatr Nov-Dec; 30(10): Pregnancy and Nutrition - Spina Bifida and Folic Acid: Ray JG et al. Association of neural tube defects and folic acid food fortification in Canada. Lancet Dec 21-28; 360(9350): Spina Bifida Association of America – Facts about Spina Bifida: Surgical-tutor.org.uk – a free online surgical resource: home.htm?system/hnep/neural_tube.htm~right home.htm?system/hnep/neural_tube.htm~righthttp:// home.htm?system/hnep/neural_tube.htm~right The Arc – Prevention of Neural Tube Defects: Wald NJ. Folic Acid and the Prevention of Neural-Tube Defects.N Engl J Med Jan 8; 350(2):

References *For anemia section Briggs, Gerald G., Freeman, Roger K., Yaffe, Sumner J. Folic Acid. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 5 th Ed. Lippincott, Williams & Wilkins: Philadelphia, PA, USA pp Briggs, Gerald G., Freeman, Roger K., Yaffe, Sumner J. Folic Acid. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 5 th Ed. Lippincott, Williams & Wilkins: Philadelphia, PA, USA pp Cotran, Kumar, Collins et al. Red Cells and Bleeding Disorders. Pathologic Basis of Disease. W.B. Saunders Company: Philadelphia, PA pp Cotran, Kumar, Collins et al. Red Cells and Bleeding Disorders. Pathologic Basis of Disease. W.B. Saunders Company: Philadelphia, PA pp Eichner, E.R. and Hillman, R.S. The evolution of anemia in alcoholic patients. Am. J. Med., 1971, 50: Eichner, E.R. and Hillman, R.S. The evolution of anemia in alcoholic patients. Am. J. Med., 1971, 50: Eichner, E.R. and Hillman, R.S. Effect of alcohol on serum folate level. J. Clin. Invest., 1973, 52: Eichner, E.R. and Hillman, R.S. Effect of alcohol on serum folate level. J. Clin. Invest., 1973, 52: Folic Acid. USP DI Vol. 1 Drug Information for the Health Care Professional. 23 rd Ed. Micromedex: Colorado, USA pp Folic Acid. USP DI Vol. 1 Drug Information for the Health Care Professional. 23 rd Ed. Micromedex: Colorado, USA pp Hillman, Robert S. Chapter 54 Hematopoietic Agents. Goodman & Gilmans Pharmacological Basis of Therapeutics. 10 th Ed. Hardman, Joel G., Limbird, Lee E., Goodman Gilman, Alfred, eds. The Mcgraw-Hill Companies, Inc.: USA pp Hillman, Robert S. Chapter 54 Hematopoietic Agents. Goodman & Gilmans Pharmacological Basis of Therapeutics. 10 th Ed. Hardman, Joel G., Limbird, Lee E., Goodman Gilman, Alfred, eds. The Mcgraw-Hill Companies, Inc.: USA pp Herbert, V., Tisman, G., Le-Teng-Go, and Brenner, L. The dU suppression test using 125-I-UDR to define biochemical megaloblastosis. Br. J. Haematol., : Herbert, V., Tisman, G., Le-Teng-Go, and Brenner, L. The dU suppression test using 125-I-UDR to define biochemical megaloblastosis. Br. J. Haematol., : Teresi, Mary E., Kailis, Stanley G., Berbatis, Constantine G. Iron Deficiency and Megaloblastic Anemias. Textbook of Therapeutics Drug and Disease Management. 6 th Ed. Herfindal, Eric T., Gourley, Dick K., eds. Williams & Wilkins: Baltimore, Maryland, USA pp. 201–220 Teresi, Mary E., Kailis, Stanley G., Berbatis, Constantine G. Iron Deficiency and Megaloblastic Anemias. Textbook of Therapeutics Drug and Disease Management. 6 th Ed. Herfindal, Eric T., Gourley, Dick K., eds. Williams & Wilkins: Baltimore, Maryland, USA pp. 201–220 Tropical Sprue. The Merck Manual Second Home Edition. Merck & Co. Inc.: Whitehouse Station, NJ, USA, Tropical Sprue. The Merck Manual Second Home Edition. Merck & Co. Inc.: Whitehouse Station, NJ, USA,